Methods of treating a mammal afflicted with excessive histamine with dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalobenzene and salts thereof

ABSTRACT

Excessive histamine in mammals is effectively relieved by the administration of dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalobenzenes. The compounds are relatively non-toxic in dosages required to alleviate such condition.

This application is a division of the copending application Ser. No. 577,098, filed May 13, 1975. The application Ser. No. 577,098 is a division of the application Ser. No. 369,567, filed June 13, 1973, now U.S. Pat. No. 3,904,622. The application Ser. No. 369,567 is a continuation-in-part of the copending U.S. Pat. application of M. L. Thominet, Ser. No. 80,211, filed Oct. 12, 1970, now abandoned. The application Ser. No. 80,211 is a continuation-in-part of the U.S. Pat. application Ser. No. 798,164, filed Feb. 10, 1969, now abandoned.

This invention relates to dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalobenzene, their non-toxic acid addition salts with a mineral or organic acid, their non-toxic quaternary ammonium salts and the process of producing these compounds. These compounds have significant pharmacological properties, particularly as spasmogenic agents and are adapted for the treatment of mammals with them.

The dialkylaminoalkyl ethers of the invention have the formula: ##SPC1##

In which m is an integer from 0 through 2 and n is an integer from 0 through 2; R and R₃ are hydrogen or lower alkyl of less than 6 carbon atoms; R₁ and R₂ are hydrogenm lower of alkyl of less than 6 carbon atoms or form a five or six membered heterocyclic radical; and X and Y are halogens.

Examples of lower alkyl having less than 6 carbon atoms are methyl, ethyl, propyl, isobutyl and amyl. Examples of five or six membered heterocyclic radicals are pyrrolidyl, piperidyl, morpholyl, piperazinyl, n-alkylpiperidyl and imidazolyl. The halogens X and Y may be the same or different; for example, they may be fluorine, chlorine or bromine.

The acid addition salts of the dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalobenzene are those produced by reacting the base with a mineral or organic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid, or ethane sulfonic acid. The quaternary ammonium salts may be obtained by reacting the benzamide with an aliphatic or aromatic alkylating agent, such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, methyl benzene sulfonate, methyl p-toluene sulfonate, ethyl bromide, propyl bromide or benzyl chloride.

The dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalobenzene amides of this invention are produced by acetylating a monoether of pyrocatechol, then halogenating the compound obtained, then deacetylating the compound and treating it with an alkylaminoalkyl chloride.

A more comprehensive understanding of this invention is obtained by reference to the following examples:

EXAMPLE I (2'-DIETHYLAMINOETHOXY- 2-METHOXY-3,5-DICHLOROBENZENE HYDROCHLORIDE

STAGE A: 3,5-dichloroguaiacol

62 G OF GUAIACOL (0.5 MOLE) IS ACETYLATED IN A 250 ML BALLOON FLASK PROVIDED WITH A REFLUX CONDENSER BY MEANS OF ACETIC ANHYDRIDE, IN THE PRESENCE OF A FEW DROPS OF CONCENTRATED SULFURIC ACID. When the reaction is concluded, the sulfuric acid is neutralized with sodium acetate and then, when the solution has been cooled, the guaiacol acetate is chlorinated.

The above solution is placed in a one liter balloon flask provided with an agitator and a thermometer. 150 ml of acetic acid is then added. 160 g of chlorosuccinimide is then added in small quantities. The suspension is then heated to from 50° to 55° C and is then kept in an oven at 55° C for 117 hours.

When the reaction is complete, cooling is effected and two liters of water is added with agitation being maintained. The chlorinated derivative crystallizes. It is dried without heating, washed and deacetylated by means of 125 ml of 30% soda lye. The product is distilled and then recrystallized from petroleum ether. 66 g of 3,5-dichloroguaiacol is obtained (melting point: 62° to 62° C) (yield 68%)

STAGE B: (2'-diethylaminoethoxy)-2-methoxy-3,5-dichlorobenzene

50 g of 3,5-dichloroguaiacol (0.25 mole) is poured into a solution of sodium ethylate prepared from 6 g of sodium in 78 ml. of absolute alcohol.

39 g (0.26 mole + 10% excess) of 1-diethylamino-2-chloroethane is added to the red solution obtained.

Upon gentle heating, the solution becomes cloudy. Sodium chloride precipitates. Heating under reflux is then applied for 7 hours. Cooling is effected and then 300 ml of water and 25 ml of concentrated hydrochloric acid are added. The aqueous solution is filtered, treated with black and the base is precipitated by 40 ml of ammonia and extracted with ether. After distillation of the ether, 51 g (yield: 72%) of (2'-diethylaminoethoxy)-2-methoxy-3,5-dichlorobenzene is obtained (boiling point/7 mm: 165° to 166° C).

STAGE C: (2'-diethylaminoethoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride

The base prepared above is dissolved in 100 ml of acetone and 6 g 35% dry hydrochloric acid in 20 ml of acetone is added. (2'-diethylaminoethoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride precipitates, which is then dried without heating, washed with acetacetone and then dried. 51 g of the product is obtained (melting point: 132° to 134° C).

ANALYSIS Calculated %: C: 47.49, H: 6.09, Cl: 32.42, N: 4.26; Actual %: C: 47.31, H: 6.14, Cl: 32.24, N: 4.18.

EXAMPLE II (3'-DIMETHYLAMINOPROPOXY)-2-METHOXY-3,5-DICHLOROBENZENE HYDROCHLORIDE

Stage A is similar to that described in Example I.

STAGE B: (3'-dimethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene

63 g of 3,5-dichloroguaiacol (0.32 mole) is poured into a solution of sodium ethylate obtained from 7.5 g of sodium and 100 ml of ethyl alcohol. 44 g (0.326 mole + 10% excess) of 1-dimethylamino-3-chloropropane is added and the resulting mixture is heated under reflux for 6 hours. Precipitation of sodium chloride is observed. It is cooled and dissolved in 300 ml of water and 30 ml of concentrated hydrochloric acid. The aqueous solution is treated with black. The resulting base is precipitated by adding ammonia. It is extracted with ether, then the ether is removed and the residue is distilled.

63 g (yield 70%) of (3'-dimethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene is obtained (boiling point/ 25 mm: 190 to 195° C).

STAGE C: (3'-dimethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride

The base prepared above is dissolved in 180 ml of acetone. 7.85 g of dry hydrochloric acid dissolved in 70 ml of acetone is added. (3'-dimethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride precipitates. It is a white solid (melting point: 138° to 140° C).

ANALYSIS: Calculated %: C: 45.79, H: 5.72, Cl: 33.86, N: 4.45; Actual %: C: 45.59, H: 5.79, Cl: 33.72, N: 4.30.

EXAMPLE III (3'-DIETHYLAMINOPROPOXY)-2-METHOXY-3,5-DICHLOROBENZENE HYDROCHLORIDE

Stage A is similar to that described in Example I.

STAGE B: (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene

The 66 g of 3,5-dichloroguaiacol (0.34 mole) prepared above is added to a solution of sodium ethylate prepared from 7 g of sodium and 130 ml of absolute alcohol. 55 g of diethylamino-3-chloropropane (0.34 mole + 10% excess) is added to the resulting red solution.

Gentle heating is applied; after 5 minutes, the solution becomes cloudy. Sodium chloride precipitates. Heating under reflux is then applied for 2 hours.

Cooling is effected and water is added. The amine precipitates. The mixture is decanted and extracted a number of times with methylene chloride, then the organic solution is washed by means of a 4% sodium solution and then with water. It is dried over potassium carbonate and the solvent is distilled. 96 g of (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene is obtained. (yield: 95%)

STAGE C: (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride

The base prepared above is dissolved in twice its weight of acetone.

Dry hydrochloric acid is bubbled into the same volume of acetone and this solution is poured into the base until methyl red changes color. The hydrochloride crystallizes. It is dried without heating, washed, dried in the air and then in an oven at 30° C. It is recrystallized a number of times from isopropanol. 51 g of (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride is obtained (melting point: 142° C) (yield: 48%).

ANALYSIS: Calculated %: C: 49.05, H: 6.42, Cl: 31.09, N: 4.09; Actual %: C: 49.16, H: 6.46, Cl: 30.90, N: 4.19.

EXAMPLE IV (3'-MORPHOLINOPROPOXY)-2-METHOXY-3,5-DICHLOROBENZENE HYDROCHLORIDE

Stage A is similar to that described in Example I.

STAGE B: (3'-morpholinopropoxy)-2-methoxy-3,5-dichlorobenzene

54 g of 3,5-dichloroguaiacol (0.28 mole) is added to sodium ethylate produced by reacting 6.44 g of sodium on 84 ml of ethyl alcohol. 51 g (0.28 mole + 10% excess) of 1-chloro-3-morpholinopropane is added to the resulting solution. The mixture is heated under reflux for 8 hours. Precipitation of sodium chloride is observed. Cooling is effected and then the mixture is dissolved in 300 ml of water and 30 ml of concentrated hydrochloric acid. The resulting solution is filtered, then ammonia is added to precipitate the base which is extracted with ether. The ether is eliminated and the residue is distilled under vacuum.

73 g (yield: 82%) of (3'-morpholinopropoxy)-2-methoxy-3,5-dichlorobenzene is obtained (boiling point/ 16 mm: 197° to 200° C).

STAGE C: (3'-morpholinopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride

The base prepared above is dissolved in 150 ml of acetone. 8.32 g of dry hydrochloric acid dissolved in 50 ml of acetone is added; (3'-morpholinopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride precipitates, which is dried without heating, washed on a filter with acetone and dried. (Weight: 73 g) (Yield: 94%) (Melting point: 183° to 184° C).

ANALYSIS: Calculated %: C: 47.12, H: 5.61, Cl: 29.87, N: 3.93; Actual %: C: 47.33, H: 5.72, Cl: 29.77, N: 3.92.

EXAMPLE V (3'DIETHYLAMINOISOPROPOXY)-2-METHOXY-3,5-DICHLOROBENZENE OXALATE

Stage A is similar to that described in Example I.

STAGE B: (3'-diethylaminoisopropoxy)-2-methoxy-3,5-dichlorobenzene

63 g of 3,5-dichloroguaiacol (0.326 mole) is added to sodium ethylate which is prepared by dissolving 7.5 g of sodium in 100 ml of alcohol. There is added to the resulting solution 54 g (0.326 mole + 10% excess) of β-chloropropyl diethylamine. The mixture is heated for 7 hours, sodium chloride precipitates. It is dissolved with 300 ml of water and 4.5 ml of concentrated hydrochloric acid. The solution is filtered and 60 ml of ammonia is added. The precipitated base is extracted with ether. The ether is eliminated and the residue is distilled.

70 g (yield: 7 to 10%) of (3'-diethylaminoisopropoxy)-3,5-dichlorobenzene is obtained (boiling point/ 5 mm: 166° to 167° C).

STAGE C: (3'-diethylaminoisopropoxy)-2-methoxy-3,5-dichlorobenzene oxalate

The base prepared above is dissolved in 130 ml of absolute alcohol; 21 g of oxalic acid which is previously dissolved in 40 ml of alcohol is added. (3'-diethylaminoisopropoxy)-2-methoxy-3,5-dichlorobenzene oxalate precipitates, which is dried without heating, washed with alcohol and dried. (Melting point: 128° C).

ANALYSIS: Calculated %: C: 48.48, H: 5.81, Cl: 17.93, N: 3.53; Actual %: C: 48.28, H: 5.98, Cl: 17.80, N: 3.39.

EXAMPLE VI (3'-DIETHYLAMINOPROPOXY)-2-METHOXY-3,5-DICHLOROBENZENE BROMOMETHYLATE

The base is prepared as described in Stages A and B of Example III.

A methanolic solution of methyl bromide (18 g of Br CH₃ for 161 ml of solution, i.e. 0.17 mole + 10% excess) is poured into 51 g (0.17 mole) of (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene dissolved in 100 ml of methanol. The solution is maintained at ambient temperature for about 90 hours. The alcohol is distilled under vacuum until a constant weight is reached. The resulting product is recrystallized from acetone. The crystals are dried without heating, washed with acetone and dried at 55° C. 43 g of white crystals of (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene bromomethylate is obtained. This product is very hygroscopic. (Melting point: 114° to 115° C) (Yield: 63%)

ANALYSIS: Calculated %: C: 44.89, H: 5.98, Br: 19.95, Cl: 17.70, N: 3.49; Actual %: C: 44.76, H: 6.10, Br: 20.03, Cl: 17.56, N: 3.28.

The high degrees of toxicity, studied on mice, have shown that the compounds, subject of the present invention, are of a toxicity which is quite compatible with therapeutic use. The following table is given by way of example:

    ______________________________________                                                        D.L. 50 in mg/kg                                                               Compound in base form                                           COMPOUND         IV      IP      SC    PO                                      ______________________________________                                         (3'-diethylaminopropoxy)-2-                                                                     34.8    181     608   737                                     methoxy-3,5-dichlorobenzene                                                                     31.3                                                          ______________________________________                                    

1. The spasmogenic action of the compounds of the invention was studied on detached guinea-pig ileum.

Taking a section of detached guinea-pig ileum, the severity of the contractions caused by increasing doses of the product under study, namely 0.1 μg/ml - 0.2 μg/ml - 0.4 μg/ml, is measured.

This study revealed the powerful spasmogenic properties of the medicaments of the invention.

2. The atropine counteracting action was also studied on detached guinea-pig ileum.

A section of ileum is suspended in aerated Tyrode liquid. (3'-diethylsminopropoxy)-2-methoxy-3,5-dichlorobenzene in a concentration of 2.10⁻ ⁷ (0.2 μg/ml) is left in contact with the muscle for 30 seconds. The resulting contractions are registered and repeated every 6 minutes until the response stabilizes.

Atropine is added to the bath 30 seconds before (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene in doses such that inhibition of the contraction of from 20 to 80% is obtained, permitting graphic determination of the counteracting dose 50.

    ______________________________________                                                               Atropine                                                                   Mean Counteracting Dose 50                                    Spasmogenic Agents                                                                                  in μg/ml                                              ______________________________________                                         (3'-diethylaminopropoxy)-2-                                                    methoxy-3,5-dichlorobenzene                                                                          1.9 (a)                                                  Spasmogenic dose:                                                                   2.10.sup..sup.-7                                                          Acetylcholine                                                                       1.10.sup..sup.-7 0.010 (a)                                                ______________________________________                                          (a) Determined over 12 tests, each section of ileum being successively         subjected to the spasmogenic action of                                         (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene, and acetylcholine                                                                               

Besides their spasmogenic properties, the medicaments of the invention have various interesting pharmacological properties which are indicated in the following table:

    __________________________________________________________________________                                 Manner                                                                             (3'-diethylamino-                                                          of ad-                                                                             propoxy)-2-meth-                                                      Doses                                                                               minis-                                                                             oxy-3,5-dichlo-                                Method             Animal                                                                             mg/kg                                                                               tration                                                                            robenzene                                      __________________________________________________________________________     Gastro-intestinal passage                                                      Measured 40 min. after admin-                                                                     Mouse                                                                              DE 50                                                                               S.C.                                                                               nil effect from                                istration of the product        0.001 mg/kg to                                 Agent: vegetable charcoal       200 mg/kg                                      Antiemetic activity                                                            Measured 30 min. (SC) or 1 hour                                                                   Dog DE 50                                                                               S.C.                                                                               16 % effect with                               (oral) after administration of  0.25 mg/kg                                     the product.                                                                   Agent: apomorphine 100 μg/kg SC                                             Cataleptic activity                                                            Measured at maximum effect, i.e.                                                                  Rat DE 50                                                                               S.C.                                                                               30 % effect with                               from 300 to 360 min. after      200 mg/kg                                      administration of the product.                                                 Traction method                                                                Measured 30 min. after admin-                                                                     Mouse                                                                              DE 50                                                                               S.C.                                                                                 197                                          istration of the product.   P.O.                                                                               40 % effect with                                                               150 mg/kg                                      Potentialisation of barbituric                                                 narcosis                    I.P.                                                                                 55.4                                         Measured 30 min. after admin-                                                                     Mouse                                                                              Index                                                   istration of the product.                                                                             2    P.O.                                                                               Index : 1.23 with                              Agent: pentobarbital 60 mg/kg IP                                                                               200 mg/kg                                      Spontaneous motivity                                                                       Winter and                                                         Measured 15 min.                                                                           Flataker                                                                              Mouse                                                                              DE 50                                                                               I.P.                                                                                 49.1                                         (I.P.) or 60 min.                                                                          test                                                               (P.O.) after admin-         P.O.                                                                               effect nil with                                istration of the                200 mg/lg                                      product.    Activograph                                                                           Mouse                                                                              DE 50                                                                               I.P.                                                                               16.1 - 19.7                                                                P.O.                                                                                 105                                          Antimescaline activity                                                         Measured 15 min. after admin-                                                                     Mouse                                                                              DE 50                                                                               I.P.                                                                               30 % effect with                               istration of the product.       100 mg/kg                                      Agent: mescaline 50 mg/kg I.M.                                                 Anti-apomorphine activity                                                      (JANSSEN test)                                                                 Measured 80 min. after admin-                                                                     Rat DE 50                                                                               S.C.                                                                               30 % effect with                               istration of the product.       600 mg/kg                                      Agent: apomorphine 1.25 mg/kg I.V.                                             Antimorphine activity                                                          (STRAUB test)                                                                  Measured 60 to 120 min. after                                                                     Mouse                                                                              DE 50                                                                               P.O.                                                                                 313                                          administration of the product.                                                 Agent: morphine 30 mg/kg S.C.                                                  Antitremorine activity                                                         (CHEN method)                                                                  Measured 60 min. after admin-                                                                     Mouse                                                                              DE 50                                                                               I.P.                                                                                 94.7                                         istration of the product.                                                      Agent: tremorine 7.5 mg/kg I.M.                                                Rotating shaft test                                                            Measured from 10 to 30 min.                                                                       Mouse                                                                              DE 50                                                                               I.P.                                                                                 71.5                                         after administration of the P.O.                                                                               18 % effect with                               product.                        200 mg/kg                                      Evasion test                                                                   (KNEIPP method)                                                                Measured 1 hour after admin-                                                                      Mouse                                                                              DE 50                                                                               I.P.                                                                                 75.9                                         istration of the product.                                                      Antiserotonine action                                                          Reduction with respect to                                                                         Dog DE 50                                                                               I.V.                                                                               19                                             reference hypertension                                                         caused by sorotonine;                                                          25 γ/kg I.V.                                                                       Electrical        S.C.                                                                               37.1                                           Anticonvulsant                                                                           crisis measured                                                                         Mouse                                                                              DE 50                                                   activity  at peak effect    P.O.                                                                               143                                                 Chemical                                                                               Agent:                                                            Anticon-                                                                            Crisis  Cardiazol                                                                            Mouse                                                                              DE 50                                                                               I.P.                                                                               84.9                                           vulsant                                                                             Measured 30                                                                            70 mg/kg       P.O.                                                                               effect nil with                                activity                                                                            min. after                                                                             I.V.               200 mg/kg                                           adminis-                                                                       tration of                                                                             Agent:                                                                 the product                                                                            Nicotine                                                                             Mouse                                                                              DE 50                                                                               I.P.                                                                               31.3                                                        2 mg/kg                                                                        I.V.           P.O.                                                                               92.9                                                Audiogenic crisis                                                         Anticon-                                                                            Measured 30 min. after                                                                       Mouse                                                                              DE 50                                                                               I.P.                                                                               18.8 - 19.7                                    vulsant                                                                             administration of the  P.O.                                                                               67                                             activity                                                                            product.                                                                       Mechanical stimulus                                                       Anal-                                                                               (HAFFNER test)                                                            gesic                                                                               Measured at peak                                                                             Mouse                                                                              DE 50                                                                               I.P.                                                                               71.5                                           activity                                                                            effect                 P.O.                                                                               # 179                                               Chemical stimulus                                                         Anal-                                                                               (phenylbenzoquinone    I.P.                                                                               22 % effect with                               gesic                                                                               test)         Mouse                                                                              DE 50    90 mg/kg                                       activity                                                                            Measured at peak       P.O.                                                                               30 % effect with                                    effect                     300 mg/kg                                            Heat stimulus                                                                 Hot plate              S.C.                                                                               45 % effect with                               Anal-                                                                               (using the JACOB, WOOL-                                                                      Mouse                                                                              DE 50    200 mg/kg                                      gesic                                                                               FE and Mac DONALD      P.O.                                                                               # 295                                          activity                                                                            method)                                                                        Measured at peak effect                                                        Histaminic hypotension                                                                           32       R = 50 to 60 %                                 Anti-                                                                               % reduction with respect                                                                         16       R = 35 to 55 %                                 hist-                                                                               to reference hypotension.                                                                    Dog 8        R = 30 to 40 %                                 aminic                 4    I.V.                                                                               R = 10 to 30 %                                 activity               2        R = 10 to 25 %                                                        1        R =  0 to 10 %                                      Blockage of the carotid                                                        arteries          16       R = 35 %                                            for 30 seconds                                                                               Dog 8        R = 32 %                                            % reduction with respect                                                                         4    I.V.                                                                               R = 31 %                                       Ortho-                                                                              to reference hyper-                                                                              2        R = 16 %                                       sympa-                                                                              tension.          1        R =  0 %                                       thetic                                                                         system                                                                              Adrenaline                                                                     % reduction or inversion                                                                     Dog DE 50                                                                               I.V.                                                                               12                                                  with respect to reference                                                      hypertension.                                                             Ortho-                                                                              Noradrenaline                                                             sympa-                                                                              % reduction with respect                                                                     Dog DE 50                                                                               I.V.                                                                               # 11                                           thetic                                                                              to reference hypertension                                                 system                                                                              Nicotine          16       R =  4 %                                            % reduction with respect                                                                         8        R = 13 %                                            to reference hyper-                                                                          Dog 4    I.V.                                                                               R =  3 %                                            tension.          2        R =  0 %                                                              1        R = 13 %                                             Acetylcholine    16       R = 33 %                                                              8        R = 37 %                                            % reduction with                                                                             Dog 4    I.V.                                                                               R = 15 %                                            respect to refer- 2        R =  5 %                                       Para-                                                                               ence hypotension  1        R =  0 %                                       sympa-                                                                         thetic                                                                              Vagal Excitation  16       R = 51 %                                       system                                                                              % reduction with                                                                             Dog 8        R = 21 %                                            respect to        4    I.V.                                                                               R = 11 %                                            reference         2        R =  0 %                                            hypotension       1        R =  0 %                                       __________________________________________________________________________

The experimental results were confirmed in clinics where the products were administered in the form of compressed tablets or phials of a pharmacologically acceptable salt. 

What is claimed is:
 1. The method of treating a mammal afflicted with excessive histamine which comprises administering to said mammal a therapeutically effective amount of a dialkylaminoalkyl ether of 2-alkoxy-3,5-dihalobenzene, a non-toxic acid addition salt thereof or a quaternary ammonium salt thereof, said dialkylaminoalkyl ether of 2-alkoxy-3,5-dihalobenzene having the formula: ##SPC2##in which m is an integer from 0 through 2; and n is an integer from 0 through 2; R is hydrogen or lower alkyl of less than 6 carbon atoms; R₃ is lower alkyl of less than 6 carbon atoms; R₁ and R₂ are hydrogen, lower alkyl of less than 6 carbon atoms or form, together with the nitrogen atoms, morpholino; and X and Y are the same halogens.
 2. The method of claim 1 in which the ether administered is (2'-diethylaminoethoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 3. The method of claim 1 in which the ether administered is (3'-dimethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 4. The method of claim 1 in which the ether administered is (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 5. The method of claim 1 in which the ether administered is (3'-morpholinopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 6. The method of claim 1 in which the ether administered is (2'-diethylamino-1'-methyl-ethoxy)-2-methoxy-3,5-dichlorobenzene oxalate.
 7. The method of claim 1 in which the ether administered is (3'-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene bromomethylate. 